Multiple Sclerosis (MS) is a debilitating demyelinating disorder that impacts the quality of life of millions of people worldwide. These defects are largel thought to be due to a chronic loss of myelin, a lipid dense structure important for normal functioning of the central nervous system. Drugs that treat MS decrease the likelihood of myelin damage, but do not stimulate myelin repair. Exercise can also lessen disability in MS patients, yet the underlying biological cause for this effect is not well understood. Additionally, it is unknown whether exercise influences either myelin repair or the maturation of oligodendroglia, the myelinating cells of the central nervous system. However, some studies in healthy adults indicate that training intricate motor skills (such as juggling) or increasing levels of exercise, correlate with increases in the size of white matter, brain areas that are heavily myelinated. Unfortunately, it is not yet clear whether exercise is influencing the myelin itself or rather othe white matter elements. Intriguingly, recent studies in rodents have found that exercise can stimulate the production of new neurons in the hippocampus, a memory area in the brain. This made us wonder whether exercise could also stimulate oligodendroglia to make new myelin. We have therefore begun to test the hypothesis that exercise influences changes in oligodendroglia that enhance myelin repair. By providing running wheels to healthy young adult female rodents for several weeks, we observed increased numbers of mature oligodendrocytes in the brains of running rodents compared to sedentary rodents. In another experiment, we exposed mice to cuprizone, a chemical that causes myelin damage. We found that cuprizone-treated mice that exercised had more myelin compared to cuprizone-treated sedentary mice. We also found that these mice had less Insulin growth factor B receptor levels, which suggests that it could play a role in protecting myelin. Our current proposal is designed to more fully evaluate the effect of exercise both on critical oligodendroglial responses such as cell division and maturation, and on the repair of myelin itself, both during cuprizone-mediated myelin damage and shortly after the removal of cuprizone, when significant myelin repair takes place. We will use whole brain imaging techniques to assess myelin, coupled with traditional histological and gene expression analyses to evaluate oligodendrocytes and myelin. We will also use transgenic mice with immature oligodendroglia that can be induced at different time points to become fluorescent, enabling us to precisely monitor the temporal dynamics of oligodendroglial differentiation and myelin repair in the exercising and sedentary mice. Together, these studies will enable us to determine how and when exercise influences myelin repair. We hope that these studies will build the foundation for future studies on the cellular signals that enable exercise to contribute o improved myelin repair. If successful, our findings could lead to a better understanding of exercise in MS treatment and the development of novel therapeutic targets for myelin repair.